Biocompatibility

Biocompatibility is the ability of a material or device to perform its intended function with an appropriate host response when placed in contact with the body. For medical devices, biocompatibility assessment is critical to ensure that materials do not cause harmful biological reactions such as toxicity, inflammation, immune response, or carcinogenicity.

Regulatory framework - ISO 10993 series:

The ISO 10993 series "Biological evaluation of medical devices" is the internationally recognized standard for biocompatibility testing. This comprehensive standard provides a risk-based framework for evaluating the biological safety of medical devices.

ISO 10993-1: Evaluation and testing within a risk management process:

This foundational document establishes the overall framework for biological evaluation:

Risk-based approach:
- Biocompatibility assessment must be integrated with ISO 14971 risk management
- Testing requirements determined by device characteristics, not automatically prescribed
- Consider intended use, nature and duration of body contact, and materials used
- Leverage existing data when possible to minimize animal testing

Biological evaluation plan:
- Systematic approach to identify and address biological risks
- Consider material characterization, toxicological risk assessment, and biological testing
- Updated throughout device lifecycle as new information becomes available

Categorization by body contact:

ISO 10993-1 classifies devices based on the nature and duration of body contact, which determines testing requirements:

Nature of body contact:

Surface devices:
- Skin contact (e.g., electrodes, external prostheses, bandages)
- Mucosal membrane contact (e.g., contact lenses, urinary catheters, endoscopes)
- Breached or compromised surfaces (e.g., wound dressings, sutures)

External communicating devices:
- Blood path indirect (e.g., IV sets, extension sets, transfer sets)
- Tissue/bone/dentin communicating (e.g., dental cements, orthopedic pins)
- Circulating blood (e.g., intravascular catheters, temporary pacemaker leads, dialyzers)

Implant devices:
- Tissue/bone (e.g., orthopedic implants, pacemakers, drug delivery devices)
- Blood (e.g., pacemaker leads, artificial hearts, heart valves, vascular grafts)

Duration of contact:

Limited contact: ≤24 hours (A)
Prolonged contact: >24 hours to 30 days (B)
Permanent contact: >30 days (C)

The combination of contact nature and duration determines the required biocompatibility endpoints to be evaluated.

ISO 10993 testing endpoints:

The standard identifies biological effects to be evaluated based on device categorization:

1. Cytotoxicity (ISO 10993-5):

What it measures: In vitro assessment of cell damage or death caused by device materials.

Testing methods:
- Extract test - Device or material extracts applied to cultured cells
- Direct contact test - Device placed directly on cell monolayer
- Indirect contact test - Device separated from cells by agarose layer

Evaluation criteria:
- Cell viability, cell morphology changes, cell membrane integrity
- Typically required for all device categories
- Often the first screening test performed

2. Sensitization (ISO 10993-10):

What it measures: Potential to cause allergic contact dermatitis or delayed hypersensitivity reactions.

Testing methods:
- Guinea pig maximization test (GPMT)
- Buehler test
- Local lymph node assay (LLNA) - in vitro alternative reducing animal use

When required:
- All devices with skin or mucosal membrane contact
- Devices with potential for patient sensitization

3. Irritation or Intracutaneous reactivity (ISO 10993-10 and 10993-23):

What it measures: Localized inflammatory response at contact or injection site.

Testing types:
- Skin irritation - Surface device contact with skin
- Eye irritation - For devices contacting mucous membranes
- Intracutaneous reactivity - Injection of extracts into skin

When required:
- Surface contact devices
- External communicating devices
- Some implant devices depending on risk assessment

4. Systemic toxicity (acute, subacute, subchronic, chronic) (ISO 10993-11):

What it measures: Systemic (whole body) toxic effects from device material exposure.

Testing durations:
- Acute toxicity - Single dose, effects observed up to 72 hours
- Subacute toxicity - Repeated exposure up to 28 days
- Subchronic toxicity - Repeated exposure 28-90 days
- Chronic toxicity - Repeated exposure >90 days (often 6-12 months)

When required:
- Prolonged or permanent contact devices
- Devices with potential for systemic material release
- Duration of testing should match or exceed intended contact duration

5. Genotoxicity (ISO 10993-3):

What it measures: Potential to damage genetic material (DNA), which could lead to mutations or cancer.

Testing battery typically includes:
- Bacterial reverse mutation test (Ames test) - Gene mutations
- In vitro mammalian cell assay - Chromosomal aberrations
- In vivo micronucleus test - Chromosomal damage in animals

When required:
- All devices with prolonged or permanent contact
- Devices where materials may be absorbed or distributed systemically
- Critical test as genotoxicity can indicate carcinogenic potential

6. Implantation (ISO 10993-6):

What it measures: Local tissue response to implanted materials.

Testing approach:
- Material implanted in appropriate tissue (e.g., muscle, bone) in animals
- Histopathological examination at specified time points
- Evaluation of inflammation, fibrosis, necrosis, other tissue reactions

When required:
- All implant devices
- Testing duration should match or exceed intended implant duration

7. Hemocompatibility (ISO 10993-4):

What it measures: Blood compatibility - interactions between blood and device materials.

Testing endpoints:
- Thrombosis - Blood clot formation
- Coagulation - Effects on clotting cascade
- Platelet activation and aggregation
- Hemolysis - Red blood cell destruction
- Complement activation - Immune system activation

When required:
- All devices with blood contact (external communicating or implant blood path)
- Critical for cardiovascular devices, blood contacting catheters, extracorporeal circuits

8. Pyrogenicity (ISO 10993-11):

What it measures: Potential to cause fever through endotoxin contamination or material release.

Testing methods:
- Bacterial endotoxin test (LAL/Limulus Amebocyte Lysate)
- Rabbit pyrogen test
- Monocyte activation test (MAT) - in vitro alternative

When required:
- Devices with blood or lymphatic system contact
- Implantable devices
- Fluid pathway devices

9. Carcinogenicity (ISO 10993-3):

What it measures: Long-term potential to cause cancer.

Testing approach:
- Long-term animal studies (typically 18-24 months)
- Only required when genotoxicity testing or other evidence suggests carcinogenic potential
- Risk assessment often used to evaluate carcinogenicity without full studies

When required:
- Rarely required for medical devices
- Permanent implants with concerning material composition or positive genotoxicity results
- Materials with known carcinogenic potential

10. Reproductive and developmental toxicity (ISO 10993-3):

What it measures: Effects on fertility, pregnancy, fetal development.

Testing types:
- Fertility and early embryonic development
- Pre- and postnatal development
- Embryo-fetal development (teratogenicity)

When required:
- Rarely required for medical devices
- Devices with potential for significant systemic material exposure
- Devices intended for use in pregnant women or children where material risk exists

11. Biodegradation (ISO 10993-9 and 10993-13):

What it measures: Breakdown of materials in biological environment and identification of degradation products.

Evaluation includes:
- Degradation rate and mechanism
- Identification and quantification of degradation products
- Toxicological assessment of degradation products

When required:
- Biodegradable or absorbable devices (e.g., absorbable sutures, bioresorbable implants)
- Devices where material degradation is expected

Material characterization and chemical testing:

ISO 10993-18: Chemical characterization of medical device materials:

Systematic identification and quantification of chemical constituents in device materials:

Objectives:
- Identify material composition and potential leachables
- Support risk assessment and testing strategy
- Enable toxicological evaluation of chemical constituents
- Reduce need for extensive biological testing when low risk materials used

Analytical techniques:
- Fourier-transform infrared spectroscopy (FTIR)
- Gas chromatography-mass spectrometry (GC-MS)
- Liquid chromatography-mass spectrometry (LC-MS)
- Inductively coupled plasma mass spectrometry (ICP-MS) for metals

Benefits:
- Chemical characterization can substitute for some biological tests when materials are well-characterized and low risk
- Identify potential toxicological concerns guiding testing strategy
- Support equivalence demonstrations to predicate devices

Extractables and leachables:

ISO 10993-12: Sample preparation and reference materials:

Proper extraction of device materials is critical for testing:

Extraction conditions:
- Extract devices using polar and non-polar solvents simulating body fluids
- Extraction temperature and duration matching intended use conditions
- Common vehicles: saline, vegetable oil, ethanol, polyethylene glycol

Extractables: Compounds that can be extracted from device under laboratory conditions.

Leachables: Compounds that actually migrate from device during clinical use (subset of extractables).

FDA guidance on biocompatibility:

"Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" (2020):

FDA recognizes ISO 10993-1:2018 and provides specific recommendations:

Risk-based approach:
- FDA supports risk-based biological evaluation
- Encourages use of existing data and chemical characterization
- Reduce unnecessary animal testing through alternatives

Endpoints evaluation:
- FDA provides matrix of recommended endpoints based on device contact categorization
- Testing should be commensurate with risk
- Use most relevant and sensitive tests for specific endpoints

Material selection:
- Prefer materials with established biocompatibility history
- When using novel materials, comprehensive testing may be required
- Document material equivalence to reduce testing burden

Chemical characterization:
- Strongly encouraged to identify extractables and assess toxicological risk
- Can potentially replace some biological testing when chemical constituents are well-understood and low risk

Common biocompatibility testing challenges:

Test article preparation:
- Ensuring extracts representative of clinical use conditions
- Sterilization effects on material biocompatibility
- Controlling for process residues (e.g., ethylene oxide, radiation byproducts)

Material equivalence:
- Demonstrating material equivalence to predicate devices
- Small formulation changes may require additional testing
- Supplier changes requiring revalidation

Extractables vs. leachables:
- Extractables testing may overestimate actual leachables
- Simulating realistic use conditions in extraction protocols
- Identifying and quantifying low-level leachables

Test variability and acceptance criteria:
- Biological test variability requiring appropriate controls
- Establishing clear pass/fail criteria
- Addressing borderline results

Regulatory expectations across regions:

United States (FDA):
- ISO 10993 recognized but not mandatory (can use alternative approaches)
- Premarket submissions should address biocompatibility appropriate to device risk
- Chemical characterization increasingly important
- Tripartite Biocompatibility Guidance (FDA/Health Canada/ISO)

European Union (EU MDR):
- Compliance with harmonized standards like ISO 10993 demonstrates conformity
- Biocompatibility addressed in General Safety and Performance Requirements (Annex I)
- Notified bodies review biocompatibility data during conformity assessment

Other regions:
- Most major regulatory authorities recognize ISO 10993 series
- Specific additional requirements may exist (e.g., China NMPA)

When is biocompatibility testing required:

New devices with new materials:
- Comprehensive testing per ISO 10993-1 matrix for device category

Material changes to existing devices:
- Changes in material formulation, supplier, or processing may require revalidation
- Extent of testing depends on significance of change

Devices with established biocompatibility:
- Materials with long history of safe use may require limited additional testing
- Literature review and equivalence demonstration may suffice

Animal testing alternatives and 3Rs:

ISO 10993 encourages the 3Rs principle:
- Replace: Use non-animal methods (in vitro, in silico) when validated and appropriate
- Reduce: Minimize number of animals through efficient study design and data sharing
- Refine: Improve procedures to minimize animal pain and distress

Validated alternatives:
- In vitro cytotoxicity replacing some in vivo tests
- Reconstructed human epidermis (RhE) for skin irritation
- Bacterial endotoxin test replacing rabbit pyrogen test
- Computational toxicology and QSAR modeling

Biocompatibility is fundamental to medical device safety. The ISO 10993 series provides a comprehensive, risk-based framework ensuring devices do not cause unacceptable biological harm while encouraging efficient use of testing resources and promoting alternatives to animal testing.